Biology subjects

Hjelm, B. E.

Publications and source records attributed to Hjelm, B. E..

4 recordsLinked to original sources

bioRxiv2025

Evidence for cPLA2 activation in Alzheimer's Disease Synaptic Pathology

BackgroundSynapses are essential for learning and memory, and their loss predicts cognitive decline in Alzheimers disease (AD). Synaptic loss is associated with excitotoxicity, neuroinflammation, amyloid-{beta}, and tau pathology, but the molecular mechanisms remain unclear. There is an urgent need to identify new targets to modify the disease and slow synaptic loss and cognitive decline. This study examines if calcium-dependent phospholipase A2 (cPLA2) is implicated in AD synaptic loss. cPLA2 catalyzes membrane phospholipids to release arachidonic acid, which can be metabolized into inflammatory eicosanoids. MethodscPLA2 levels were examined in synaptosomes isolated from the postmortem frontal cortex of individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD dementia from the Religious Orders Study (ROS). Eicosanoids in synaptosomes were analyzed using lipidomics. Immunofluorescent staining investigated cPLA2 interactions with synaptic markers. Human iPSCs-derived neurons were used to study cPLA2 overactivation after exposure to amyloid-{beta} 42 oligomers (A{beta}42O), its relationships with synaptic markers, and the effects of cPLA2 inhibitors. ResultsWe observed elevated cPLA2 (cPLA2 and cPLA2{beta}) in AD synaptosomes and positive correlations with postsynaptic density protein 95 (PSD-95) and cognitive dysfunction. Eicosanoids were increased in AD synaptosomes and correlated with cPLA2, indicating cPLA2 activity at synapses/synaptosomes. Phosphorylated cPLA2 (p-cPLA2) colocalized with PSD-95 in synaptosomes, and with postsynaptic Ca2+/calmodulin-dependent protein kinase II (CaMKII) and dendritic microtubule-associated protein 2 (MAP2) in NCI and AD brains, where their levels were reduced in AD. P-cPLA2 colocalizes with MAP2 at the neuronal soma associated with neuritic plaques and neurodegeneration in AD. A{beta}42O activates cPLA2 in human iPSCs-derived neurons, leading to p-cPLA2 relocation from the cytosol to synaptic and dendritic sites to colocalize with CaMKII and MAP2, resulting in their reduction. P-cPLA2 also colocalized with PSD-95 in A{beta}42O-exposed neurons, accompanied with increased PSD-95 intensity at soma membrane. These processes were reversed by the cPLA2 inhibitor ASB14780. ConclusionscPLA2 overactivation at synapses, dendrites, and excitatory neuronal somas is associated with synaptic loss, neuritic plaques and neurodegeneration, potentially contributing to cognitive decline in AD. Future research needs to explore the role of cPLA2 as a disease-modifying target for AD.

neuroscience↗

bioRxiv2021

Tear miRNAs identified in a murine model of Sjögren's Syndrome as potential diagnostic biomarkers and indicators of disease mechanism

ObjectiveThe tear miRNAome of the male NOD mouse, a model of ocular symptoms of Sjogrens syndrome (SS), was analyzed to identify possible tear biomarkers of the disease. MethodsMale NOD mice, aged 12-14 weeks, were used to identify tear miRNAs associated with development of autoimmune dacryoadenitis. Age-matched female NOD mice that do not develop the autoimmune dacryoadenitis characteristic of SS were used as negative controls while age- and sex-matched male BALB/c mice served as healthy controls. Total RNA was isolated from stimulated tears pooled from 5 mice per sample and tear miRNAs were sequenced and analyzed. Putative miRNA hits were validated using RT-qPCR in a separate mouse cohort, and the pathways influenced by the validated hits were identified using Ingenuity Pathway Analysis. ResultsIn comparison to tears from both healthy (male BALB/c) and negative control (female NOD) mice, initial analysis identified 7 upregulated and 7 downregulated miRNAs in male NOD mouse tears. Of these, 8 were subsequently validated by RT-qPCR in tears from additional mouse cohorts. miRNAs previously implicated in SS pathology included mmu-miR-146a/b-5p, which were significantly downregulated in the male NOD mouse tears, as well as mmu-miR-150-5p and mmu-miR-181a-5p, which were upregulated in the male NOD mouse tears. All other validated hits including the upregulated miR-181b-5p and mmu-miR-203-3p, as well as the downregulated mmu-miR-322-5p and mmu-miR-503-5p, represent novel putative indicators of autoimmune dacryoadenitis in SS. ConclusionsA panel of differentially expressed miRNAs were identified in tears of SS model male NOD mice, including some never previously linked to SS. These may have potential utility as diagnostic biomarkers for ocular symptoms of SS; evaluation of the pathways influenced by these dysregulated miRNAs may also provide further insights into SS pathogenesis.

immunology↗

bioRxiv2021

The Foundational data initiative for Parkinsons disease (FOUNDIN-PD): enabling efficient translation from genetic maps to mechanism

The FOUNdational Data INitiative for Parkinsons Disease (FOUNDIN-PD) is an international collaboration producing fundamental resources for Parkinsons disease (PD). FOUNDIN-PD generated a multi-layered molecular dataset in a cohort of induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons, a major affected cell type in PD. The lines were derived from the Parkinsons Progression Markers Initiative study including participants with PD carrying monogenic PD (SNCA) variants, variants with intermediate effects and variants identified by genome-wide association studies and unaffected individuals. We generated genetic, epigenetic, regulatory, transcriptomic, and longitudinal cellular imaging data from iPSC-derived DA neurons to understand molecular relationships between disease associated genetic variation and proximate molecular events. These data reveal that iPSC-derived DA neurons provide a valuable cellular context and foundational atlas for modelling PD genetic risk. We have integrated these data into a FOUNDIN-PD data browser (https://www.foundinpd.org) as a resource for understanding the molecular pathogenesis of PD.

genomics↗

bioRxiv2019

Spreading depolarization and repolarization during cardiac arrest as an ultra-early marker of neurological recovery in a preclinical model

Spreading depolarization (SD) accompanies numerous neurological conditions, including migraine, stroke, and traumatic brain injury. There is significant interest in understanding the relationship between SD and neuronal injury. However, characteristics underlying SD and repolarization (RP) induced by global cerebral ischemia (e.g., cardiac arrest (CA)) and reperfusion are not well understood. Quantifying features of SD and RP during CA and cardiopulmonary resuscitation (CPR) may provide important metrics for diagnosis and prognosis of neurological injury from hypoxia-ischemia. We characterized SD and RP in a rodent model of asphyxial CA+CPR using a multimodal platform including electrocorticography (ECoG) and optical imaging. We detected SD and RP by (1) alternating current (AC), (2) direct current (DC), and (3) optical imaging of spreading ischemia, spreading edema, and vasoconstriction. Earlier SD (r=-0.80; p<0.001) and earlier RP (r=-0.71, p<0.001) were associated with better neurological recovery after 24hrs. SD+RP onset times predicted good vs poor neurological recovery with 82% sensitivity and 91% specificity. To our knowledge, this is the first preclinical study to link SD and RP characteristics with neurological recovery post-CA. These data suggest that SD and RP may be ultra-early, real-time prognostic markers of post-CA outcome, meriting further investigation into translational implications during global cerebral ischemia.

neuroscience↗